EP1841423B1 - Methodes d'utilisation comme analgesiques de 1-benzyl-1-hydroxy-2,3-diamino- propyl amines, d'amides d'acide 3-benzyl-3-hydroxy-2-amino-propionique et de leurs composes - Google Patents

Methodes d'utilisation comme analgesiques de 1-benzyl-1-hydroxy-2,3-diamino- propyl amines, d'amides d'acide 3-benzyl-3-hydroxy-2-amino-propionique et de leurs composes Download PDF

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EP1841423B1
EP1841423B1 EP06719390A EP06719390A EP1841423B1 EP 1841423 B1 EP1841423 B1 EP 1841423B1 EP 06719390 A EP06719390 A EP 06719390A EP 06719390 A EP06719390 A EP 06719390A EP 1841423 B1 EP1841423 B1 EP 1841423B1
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compound
threo
hydroxy
mmol
yield
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EP1841423A2 (fr
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Bertrand Leblond
Eric Beausoleil
Thierry Taverne
John E. Donello
Fabien Schweighoffer (Jacques)
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Allergan Inc
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Allergan Inc
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
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Definitions

  • the present invention relates to the use of
  • PDMP 1-Phenyl-2-decanoylamino-3-morpholino-1-propanol
  • glucosylceramide (GlcCer) formation by inhibiting the enzyme GlcCer synthase, thereby lowering the level of glycosphingolipids.)
  • the isomers most active have the R,R -(D- threo )-configuration. Four enantiomers are produced during the synthesis. Because only the D- threo enantiomers are active in inhibiting the glucosylceramide synthase, resolution of the active D- threo inhibitors was performed by chiral chromatography.
  • D- threo -PDMP has antitumor activity via inhibition of glycosphingolipid biosynthesis as described by Inokuchi J., Cancer Letters 38(1-2), 23-30, 1987 .
  • D -threo -PDMP suppresses synaptic function by Mizutani A. et al., Biochem. Biophys. Res. Commun., 222, 494-498, 1996 .
  • L- threo -PDMP is an agent for treating neuronal diseases WO 95/05177 . This compound is also described to be an agent for protecting brain in US 6407064 . Moreover treatment with L- threo -PDMP after transient forebrain ischemia in rats ameliorated the deficit of a well learned spatial memory by an 8-arm maze task, suggesting a potential for neurodegenerative disorders as described by Inokuchi et al., Ann. N.Y. Acad. Sci., 845(1), 219-224, 1998 and JP 10324671 (Seikagaku Kogyo Co.).
  • L-threo -PDMP enantiomerically pure (1 S ,2 S )-1-phenyl-2-decanoylaimno-3-moipholmo-1-propanol
  • WO 95/05177 (which corresponds to EP 0 720 852 ) discloses the use of 2-acylaminopropanol derivatives for the treatment of neuronal diseases.
  • these diseases inter alia are peripheral nervous system diseases, e.g. polyneuropathy caused by cacochymia, mechanical neuropathy and toxic neuropathy.
  • peripheral nervous system diseases e.g. polyneuropathy caused by cacochymia, mechanical neuropathy and toxic neuropathy.
  • L- threo -PDMP further stereoisomers of PDMP such as DL- erythro -PDMP and D- threo -PDMP are described.
  • D- threo -1-phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (P4 or PPPP) analogues were first obtained by a Mannich reaction as described Abe, A. et al., J. Biochem., 111, 191-196, 1992 or US 5916911 and WO 2001004108 .
  • Preparation of D- threo -4'-hydroxy-P4 one of the most potent inhibitor of GCS, was described by Lee, L. et al., J. Biol.
  • Novel prodrugs of P4 derivatives were described in US 20020198240 and WO 2002062777 .
  • Synthesis of enantiomerically pure of D- threo -ethylenedioxy-P4 and D- threo - p -methoxy-P4 were described by Husain A. and Ganem B., Tetrahedron Lett., 43, 8621-8623, 2002 .
  • the key step is a highly syn- selective additions of aryl Grignard reagents to Garner aldehyde.
  • methyl isocyanoacetate CNCH 2 CO 2 Me was treated with pyrrolidine and the amide was treated with 1,4-benzodioxane-6-carboxaldehyde, followed by hydrolysis of the oxazoline using HCl in methanol, reduction of the keto group of amide II using LiAlH 4 , and acylation with palmitoyl chloride to give D,L- threo -ethylenedioxy-P4 III.
  • Synthesis of enantiopure P4 analogues were described in WO 2003008399 (Genzyme Corp.).
  • D- threo -ethylenedioxy-P4 was prepared via a multistep synthetic sequence starting from S -(+)-Ph glycinol, phenyl- ⁇ -bromoacetate, 1,4-benzodioxan-6-carboxaldehyde, pyrrolidine and palmitoyl chloride.
  • New D- threo -P4 analogues that bear ether substituents on the aromatic ring have been recently synthesized from D-serine and found to suppress neurite extension in an embryonic insect cell line as described by Slavish., J. P. et al., Bioorg. Med. Chem. Lett., 14, 1487-1490, 2004 .
  • the present invention is directed to the use of the compounds shown below as analgesics for the manufacture of a medicament for treating chronic pain by administering to a mammal, in need of such administration a pharmaceutical composition containing one or more of the compounds or their pharmaceutically acceptable salts.
  • the present invention is still further directed to pharmaceutical compositions containing the compounds shown below except the reference compounds and all other pharmaceutically acceptable salts of these compounds for use in the treatment of chronic pain.
  • the designation "DL” or “(+/-)” or “ ( ⁇ )” in this application includes the pure dextrorotatory enantiomer, the pure levorotatory enantiomer and all racemic mixtures, including mixtures where the two enantiomers are present in equal or in unequal proportions. Moreover, for simplicity sake in many of the structural formulas, such as in the example below, only one of the enantiomers is actually shown but when the designation "DL” (or “(+/-)” or “ ( ⁇ )”) appears it also includes the enantiomeric form (mirror image) of the structure actually shown in the formula.
  • the compounds used in the present invention may already be shown as hydrochloride salts.
  • the compounds may also exist in salt free form or may form salts with pharmaceutically acceptable acids, other than hydrochloric acid, and such pharmaceutically acceptable salts are also within the scope of the invention.
  • the compounds used in the invention have analgesic activity in mammals.
  • An art-accepted model or assay for measuring an analgesic effect of a compound in chronic pain is the model known as Kim and Chung 1992, Pain 150, pp 355-363 ( Chung model).
  • This model involves the surgical ligation of the L5 (and optionally the L6) spinal nerves on one side in experimental animals. Rats recovering from the surgery gain weight and display a level of general activity similar to that of normal rats. However, these rats develop abnormalities of the foot, wherein the hindpaw is moderately everted and the toes are held together. More importantly, the hindpaw on the side affected by the surgery appears to become sensitive to low-threshold mechanical stimuli and will perceive pain instead of the faint sensation of touch.
  • rats are anesthetized before surgery.
  • the surgical site is shaved and prepared either with betadine or Novacaine.
  • Incision is made from the thoracic vertebra Xlll down toward the sacrum.
  • Muscle tissue is separated from the spinal vertebra (left side) at the L4 - S2 levels.
  • the L6 vertebra is located and the transverse process is carefully removed with a small rongeur to expose the L4 - L6 spinal nerves.
  • the L5 and L6 spinal nerves are isolated and tightly ligated with 6-0 silk thread. The same procedure is done on the right side as a control, except no ligation of the spinal nerves is performed.
  • the wounds are sutured.
  • a small amount of antibiotic ointment is applied to the incised area, and the rat is transferred to the recovery plastic cage under a regulated heat-temperature lamp.
  • the test drugs are administered by intraperitoneal (i.p.) injection or oral gavage (p.o.).
  • i.p. administration the compounds are formulated in H 2 O and given in a volume of 1 ml/kg body weight by injecting into the intraperitoneal cavity.
  • p.o. administration the compounds are formulated in H 2 O and given in a volume of 1 ml/kg body weight using an 18-gauge, 3 inch gavage needle that is slowly inserted through the esophagus into the stomach.
  • Tactile allodynia is assessed via von Frey hairs, which are a series of fine hairs with incremental differences in stiffness. Rats are placed in a plastic cage with a wire mesh bottom and allowed to acclimate for approximately 30 minutes. To establish the pre-drug baseline, the von Frey hairs are applied perpendicularly through the mesh to the mid-plantar region of the rats' hindpaw with sufficient force to cause slight buckling and held for 6-8 seconds. The applied force has been calculated to range from 0.41 to 15.1 grams. If the paw is sharply withdrawn, it is considered a positive response. A normal animal will not respond to stimuli in this range, but a surgically ligated paw will be withdrawn in response to a 1-2 gram hair.
  • the 50% paw withdrawal threshold is determined using the method of Dixon, W.J., Ann. Rev. Pharmacol. Toxicol. 20:441-462 (1980 ). Tactile allodynia is measured prior to and 15, 30, and 60 minutes after drug administration. The post-drug threshold is compared to the pre-drug threshold and the percent reversal of tactile sensitivity is calculated based on a normal threshold of 15.1 grams.
  • Table 1 below indicates the degree of pain reversal obtained in the Chung model with exemplary compounds used in accordance with the invention.
  • the intraperitonial (i.p.) and/or intravenous (iv) administration of the compounds was in doses ranging from 1 ⁇ g/kg to 300 ⁇ g/kg or 3mg/kg PO and the peak percentage of reversal of allodynia was measured at 15, 30 or 60 minutes after administration, as is indicated in the table. Data are expressed as the highest % allodynia reversal (out of 3 time points: 15 min, 30 min, or 60 min. post-drug) with a minimum of a 20% allodynia reversal in the rat Chung model. Comparisons between groups (drug treated vs.
  • the compounds used in the invention are administered at pharmaceutically effective dosages.
  • dosages are normally the minimum dose necessary to achieve the desired therapeutic effect; in the treatment of chronic pain, this amount would be roughly that necessary to reduce the discomfort caused by the pain to tolerable levels.
  • doses generally will be in the range 0.1-5000 mg/day; more preferably in the range 1 to 3000 mg/day, still more preferably in the range of 10 mg to 1000 mg/day.
  • the actual amount of the compound to be administered in any given case will be determined by a physician taking into account the relevant circumstances, such as the severity of the pain, the age and weight of the patient, the patient's general physical condition, the cause of the pain, and the route of administration.
  • the patient will be given the compound in a composition orally in any pharmaceutically acceptable form, such as a tablet, liquid, capsule, powder and the like.
  • a composition orally in any pharmaceutically acceptable form, such as a tablet, liquid, capsule, powder and the like.
  • other routes may be desirable or necessary, particularly if the patient suffers from nausea.
  • Such other routes may include transdermal, intraperitonial, parenteral, subcutaneous, intranasal, intrathecal, intramuscular, intravenous and intrarectal modes of delivery and the present invention extends to pharmaceutical compositions adapted for such deliveries.
  • Pharmaceutical compositions tend to contain a pharmaceutically acceptable excipient.
  • excipient are well known in the art and may be a carrier or a diluent; this is usually mixed with the active compound, or permitted to dilute or enclose the active compound.
  • the carrier may be solid, semi-solid, or liquid material that acts as an excipient or vehicle for the active compound.
  • the formulations of the compositions may also include wetting agents, emulsifying agents, preserving agents, sweetening agents, and/or flavoring agents. If used as in an ophthalmic or infusion format, the formulation will usually contain one or more salt to influence the osmotic pressure of the formulation.
  • the compound used in the invention are per se known in the art and can be obtained from commercial sources or by the synthetic processes described in the pertinent references (primarily in Shin, S. et al., [Tetrahedron asymmetry, 11, 3293-3301, 2000 ] and US 20030153768 ) and noted in the Background Art section of the present application.
  • the majority of the compounds were nevertheless synthesized and their preparations are described below.
  • the organic layer was removed; two more extracts were combined and dried over MgSO 4 , filtered and evaporated. Concentration afforded to a crude product as a yellow oil.
  • the white suspension was then concentrated to remove THF and taken back up in a mixture of 300 mL CH 2 Cl 2 and 1N aqueous hydrochloric acid (50 mL).
  • the organic layer was removed, combined with additional CH 2 Cl 2 extracts (4 x 200 mL) and dried over MgSO 4 , filtered and evaporated.
  • the hydrochloride salt was obtained from 100 mg of the free base in diethylether at 0°C using a solution 0.3 M HCl in diethylether. The precipitate was filtered and dry to give benzyl L- threo- 1-hydroxy-3-morpholino-1-phenylpropan-2-ylcarbamate hydrochloride Compound 1 as a white solid (70 mg, 65 % yield).
  • a three neck, 250 mL round bottom flask was equipped with a low temperature thermometer and two (2) equalizing dropping funnels. One of these was connected to a nitrogen line and charged with a solution of (( R )-1-(( S )-1-phenylethyl)aziridin-2-yl)methanol EBE 06046 (7.0 g, 39.5 mmol) in CH 2 Cl 2 (75 mL), the other was charged with a solution of DMSO (9.25 g, 118.5 mmol) in CH 2 Cl 2 (11 mL).
  • EBE 06070A the acetate salt of (2 R )-amino-3-morpholin-4-yl-(1 R )-phenyl-propan-1-ol (0.279 g, 98 % yield).
  • solution of EBE 06070A the acetate salt of (2 R )-amino-3-morpholin-4-yl-(1 R )-phenyl-propan-1-ol (0.100 g, 0.338 mmol) in ethanol (1 mL) was added a solution of HCl (0.8 M, 0.930 mL) in EtOH.
  • PDMP 1-plienyl-2-decanoylanuno-3-moupliolino-1-propanol
  • Enantiomerically pure D- threo -PDMP has been reported by Mitchell, Scott A.[ J. Org. Chem., 63 (24), 8837-8842, 1998 ]; Miura, T. et al, [Bioorg. Med. Chem., 6,1481-1498, 1998 ]; Shin, S. et al., [Tetrahedron asymmetry, 11, 3293-3301, 2000 ]; WO 2002012185 .
  • Synthesis of enantiomerically pure L- threo -PDMP is described by Mitchell, Scott A., [J. Org. Chem., 63 (24), 8837-8842, 1998 ]; Miura, T. et al, [Bioorg. Med. Chem., 6, 1481-1498,1998 ]; and JP-A-9-2168586 .

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Claims (13)

  1. Utilisation d'un composé choisi dans le groupe constitué des composés illustrés par les formules structurales ci-dessous
    Figure imgb0101
    Figure imgb0102
    Figure imgb0103
    Figure imgb0104
    Figure imgb0105
     ou de tout sel pharmaceutiquement acceptable de celui-ci pour la fabrication d'un médicament antalgique destiné au traitement d'une douleur chronique chez un mammifère ayant besoin d'un tel traitement.
  2. Utilisation selon la revendication 1, où le médicament antalgique comprend le composé ayant la formule
    Figure imgb0106
     ou tout sel pharmaceutiquement acceptable de celui-ci.
  3. Utilisation selon la revendication 1, où le médicament antalgique comprend le composé ayant la formule
    Figure imgb0107
     ou tout autre sel pharmaceutiquement acceptable dudit composé.
  4. Utilisation selon la revendication 1, où le médicament antalgique comprend le composé ayant la formule
    Figure imgb0108
     ou tout autre sel pharmaceutiquement acceptable dudit composé.
  5. Utilisation selon la revendication 1, où le médicament antalgique comprend le composé ayant la formule
    Figure imgb0109
     ou tout autre sel pharmaceutiquement acceptable dudit composé.
  6. Utilisation selon la revendication 1, où le médicament antalgique comprend le composé ayant la formule
    Figure imgb0110
     ou tout autre sel pharmaceutiquement acceptable dudit composé.
  7. Utilisation selon la revendication 1, où le médicament antalgique comprend le composé ayant la formule
    Figure imgb0111
     ou tout autre sel pharmaceutiquement acceptable dudit composé.
  8. Utilisation selon la revendication 1, où le médicament antalgique comprend le composé ayant la formule
    Figure imgb0112
     ou tout autre sel pharmaceutiquement acceptable dudit composé.
  9. Utilisation selon la revendication 1, où le médicament antalgique comprend le composé ayant la formule
    Figure imgb0113
     ou tout autre sel pharmaceutiquement acceptable dudit composé.
  10. Utilisation selon la revendication 1, où le médicament antalgique comprend le composé ayant la formule
    Figure imgb0114
     ou tout autre sel pharmaceutiquement acceptable dudit composé.
  11. Utilisation selon la revendication 1, où le médicament antalgique comprend le composé ayant la formule
    Figure imgb0115
     ou tout autre sel pharmaceutiquement acceptable dudit composé.
  12. Utilisation selon la revendication 1, où le médicament antalgique comprend le composé ayant la formule
    Figure imgb0116
     ou tout autre sel pharmaceutiquement acceptable dudit composé.
  13. Utilisation selon la revendication 1, où le médicament antalgique comprend le composé ayant la formule
    Figure imgb0117
     ou tout autre sel pharmaceutiquement acceptable dudit composé.
EP06719390A 2005-01-26 2006-01-25 Methodes d'utilisation comme analgesiques de 1-benzyl-1-hydroxy-2,3-diamino- propyl amines, d'amides d'acide 3-benzyl-3-hydroxy-2-amino-propionique et de leurs composes Active EP1841423B1 (fr)

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US20120225881A1 (en) 2012-09-06
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US20130005717A1 (en) 2013-01-03
US8153666B2 (en) 2012-04-10
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ATE460159T1 (de) 2010-03-15
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US20090088433A1 (en) 2009-04-02
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US9828349B2 (en) 2017-11-28
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